Background <p>Deep vein thrombosis (DVT) is a feared postoperative complication following knee arthroplasty. However, the incidence of acute DVT, associated early risk stratification models, and optimal thromboprophylaxis after unicompartmental knee arthroplasty (UKA) remain unclear. This study aimed to comprehensively evaluate the perioperative dynamics of systemic-inflammatory and hemostatic molecular markers in patients with knee osteoarthritis undergoing UKA and to analyze their association with the occurrence of acute DVT.</p> Methods <p>The first multi-center prospective study enrolled consecutive patients undergoing unilateral UKA without routine postoperative pharmacological thromboprophylaxis from three institutions (two for derivation and one for external validation). Systemic-inflammatory and hemostatic molecular markers were measured at admission, 2-hour, 1-day, and 3-day post-UKA. Lower-extremity ultrasound was routinely conducted prior to and at 4–5 days following UKA to detect asymptomatic and symptomatic DVT. Temporal trends in these biomarkers and their relationship with acute DVT were analyzed. A nomogram was then developed to visualize individualized near-term risk stratification of acute postoperative DVT. Finally, a retrospective cohort of UKA-treated patients who received routine thromboprophylaxis was enrolled to evaluate the risk stratification performance of the identified indicators in an anticoagulated population.</p> Results <p>The derivation cohort included 87 patients (mean age 67.8 ± 6.5 years, 78.2% female), of whom 21 (24.1%) developed acute postoperative DVT (20 asymptomatic and 1 symptomatic). Multivariate Firth’s penalized logistic regression identified that higher body mass index (BMI), and elevated postoperative day 3 levels of interleukin (IL)-6, thrombin-antithrombin complex (TAT), and plasmin-α2 plasmin inhibitor complex (PIC) independently associated with an increased risk of acute DVT detected at 4–5 days post-UKA. A nomogram incorporating these four indicators demonstrated good discriminative ability, calibration, and exploratory net benefit. These findings were further validated in an independent external cohort (<i>n</i> = 42; mean age 67.2 ± 7.7 years; 69% female; DVT incidence, 23.8%) and in a separate cohort of 135 patients (mean age 66.4 ± 6.8 years; 77% female; DVT incidence, 20.7%) who received routine thromboprophylaxis.</p> Conclusion <p>A preliminary nomogram incorporating BMI and postoperative day 3 levels of IL-6, TAT, and PIC serves as a promising auxiliary tool for near-term risk stratification of acute DVT detected at 4–5 days following UKA.</p>